Coronary heart disease (CHD) is the number one killer of women in the United States. Hormone replacement therapy (HRT) with estrogen (E) and progesterone (P) should probably no longer be considered cardioprotective. In fact, data from the HERS and WHI studies indicate E+P may increase myocardial infarction (MI) and stroke despite its beneficial effects on cholesterol levels. Since blood platelets play a central role in the pathophysiology of MI and stroke, these findings raise questions about the effect of HRT on platelet thrombus formation in coronary vessels. Our published and preliminary data show that 1) female platelets are hyperreactive compared to male platelets, 2) sex hormones enhance platelet reactivity, 3) platelets express estrogen receptor (ER) beta and ER alpha, 4) functional platelet polymorphisms are risks for CHD, and 5) there are pharmacogenetic interactions between functional polymorphisms of platelet genes and specific cardiovascular therapies (aspirin, statins, and GPIIb-Illa blockers). Because women are at least as predisposed as men to genetic influences on CHD development, we hypothesize that inherited platelet variants dictate which postmenopausal women are susceptible to the prothrombotic effects of HRT. Our goal in this proposal is to identify genetic predictors of CHD events in women. We will perform a case-control study on the Observational Study of the Women's Health Initiative, analyzing DNA from 1,060 women who have experienced a CHD death or documented nonfatal MI (cases) and from 2,120 controls not having a CHD event. With this large number of CHD cases and controls we will test for associations between functional platelet polymorphisms and CHD events (Aim 1) and interactions between these polymorphisms and HRT as a risk for CHD events (Aim 2). We have assembled an excellent group of investigators and have an extremely valuable resource, putting us in a unique position to achieve these goals and our long-term goal of optimizing the prevention and management of CHD in women.